Rheumatoid arthritis (RA) represents one of the most common forms of inflammatory arthritis worldwide. Among U.S. Veterans, RA is associated with substantial morbidity, accelerated mortality, and rapidly rising treatment costs. Fortunately, there have been substantial recent gains in our understanding of RA pathogenesis including insight into the role of antigen-specific autoantibodies in disease propagation. Preliminary evidence from our group and others suggest that select autoantibodies may serve as robust biomarkers for disease progression and indeed may actually directly mediate the joint damage that characterizes RA. Moreover, our preliminary data suggests that antigen-specific autoantibody responses in RA may be 'shaped' by environmental factors including cigarette smoking and periodontitis (PD), modifiable factors that could be targeted in future strategies of disease treatment and/or prevention. Supported now by substantial preliminary data, our overarching hypothesis is that environmental factors directly impact the formation of specific autoantigens and tolerance loss in RA, leading to adaptive immune responses that in turn have profound implications in RA. We plan to test our central hypothesis and, thereby, accomplish the objectives of this application by pursuing the following three specific aims: Aim 1 will examine the associations of antigen-specific autoantibody responses in RA with radiographic disease progression. Studies will initially be conducted using data and serum samples already available for patients enrolled in the recently completed multinational VA Cooperative Study Program (CSP) 551 Study. Analyses will be replicated in an additional RA cohort to mitigate false positive findings. This aim will include preliminary studies exploring whether select autoantibodies stimulate osteoclast function and bone resorption, pathologic features of bony erosion in RA. Aim 2 will examine associations of subgingival microbiome composition (altered in the context of PD) with RA risk. These analyses will leverage data and biosamples available (including subgingival bacterial plaque samples) as part of the largest case-control study ever conducted examining the association of PD with RA risk led by the PI. Aim 3 will then examine to what extent environmental factors (both smoking and PD) shape autoantibody responses in RA. Studies in this aim will include initial explorations of whether select subgingival bacteria influence antigen-specific responses of circulating T-cells, thus promoting systemic autoimmunity in RA. The questions proposed in this study are highly significant; addressing scientific questions and current gaps in our understanding that have a high probability of altering the way the RA is approached in clinical management in addition to shaping a future research agenda.